Intestinal microbiome and NAFLD: molecular insights and therapeutic perspectives

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of dysregulated lipid and glucose metabolism, which is often associated with obesity, dyslipidemia and insulin resistance. In view of the high morbidity and health risks of NAFLD, the lack of effective cure has drawn great attention. In recent years, a line of evidence has suggested a close linkage between the intestine and liver diseases such as NAFLD. We summarized the composition and characteristics of intestinal microbes and reviewed molecular insights into the intestinal microbiome in development and progression of NAFLD. Intestinal microbes mainly include bacteria, archaea, viruses and fungi, and the crosstalk between non-bacterial intestinal microbes and human liver diseases should be paid more attention. Intestinal microbiota imbalance may not only increase the intestinal permeability to gut microbes but also lead to liver exposure to harmful substances that promote hepatic lipogenesis and fibrosis. Furthermore, we focused on reviewing the latest ''gut-liver axis''-targeting treatment, including the application of antibiotics, probiotics, prebiotics, synbiotics, farnesoid X receptor agonists, bile acid sequestrants, gut-derived hormones, adsorbents and fecal microbiota transplantation for NAFLD. In this review, we also discussed the potential mechanisms of ''gut-liver axis'' manipulation and efficacy of these therapeutic strategies for NAFLD treatment.

Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders

“…107 Microbiomes of patients with NASH and obese mice are also enriched in Escherichia coli, which are associated with increased endogenous production of ethanol, which can increase intestinal permeability. [108][109][110] Moreover, alterations in bile acid metabolism brought about by obesity-associated microbiota profiles contribute to pathogenesis of NAFLD and NASH (for reviews, see Hu et al 111 and Chavez-Talavera et al 112 ). However, germ-free mice are more and less susceptible to fatty liver and steatohepatitis, depending on the strain and the diets administered.…”

Ileal bile acid transporter inhibitor improves hepatic steatosis by changing the gut microbiota dysbiosis in NAFLD model mice

“…In enterocytes in the ileum, activation of FXR by BAs reabsorbed by IBAT releases FGF15 (the mouse ortholog of human FGF19) into the portal circulation. FGF15 binds its receptor broblast growth factor receptor 4 (FGFR4), and inhibits CYP7A1, thus repressing bile acid synthesis in hepatocytes [7]. Here, we identi ed an important role of IBATi as regulator of hepatic lipid metabolism through the gut microbiota, in addition to its role in bile acid metabolism.…”

“…There is an anatomical link between the intestine and liver via the hepatic portal system. Based on this connection between the intestine and liver, also termed the gut-liver axis, gut microbiota and their metabolic products may in uence liver pathology and this axis plays a pivotal role in the pathogenesis of NAFLD [7,8]. The human gut microbiota contains over 100 fold more genes than its host and has been also suggested to be an important environmental factor involved in the pathogenesis of NAFLD [9].…”

New Insights into the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Gut-Derived Lipopolysaccharides and Oxidative Stress

“…Many antibiotics have regulatory effects on intestinal microbiota and are of benefit to NAFLD [73]. For example, oral treatment with Cidomycin was found to promote the small intestine transit rate and reduce serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor alpha (TNF-α) in a NASH mouse model, indicating the potential of Cidomycin in alleviating the severity of NASH via intestinal microbiota modulation [74].…”